Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02185352 |
| Other study ID # |
201402059MIPD |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
April 21, 2014 |
| Est. completion date |
November 2022 |
Study information
| Verified date |
May 2021 |
| Source |
National Taiwan University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The primary objective of A-PLUS trial is to evaluate and compare the efficacy of induction
BEEP (bevacizumab preconditioning followed by etoposide and cisplatin) followed by whole bran
radiotherapy (WBRT) with WBRT alone in the controlling of brain metastases (BM) in metastatic
breast cancer (MBC) patients who have not previously received WBRT.
In past 2 years, the research team has demonstrated that BEEP regimen is a highly effective
treatment for brain metastases of breast cancer progressing from WBRT by a multi-center phase
II study (ClinicalTrials.gov Identifier: NCT01281696). The basic concept of preconditioning,
as referred to starting bevacizumab 1 day before chemotherapy, is that the effect of
bevacizumab induced tumor vascular normalization takes time to mature.
The investigators hypothesized that as induction BEEP decreased the size of brain tumors, the
effectiveness of WBRT would be maximized. The investigators expect this integrated approach
will do greater benefit to MBC patients with BM, irrespective of subtype.
Description:
Brain metastasis (BM) occurs in about 20% to 35% of metastatic breast cancer (MBC) patients.
In contrast to recent advances in systemic treatment of MBC, there is much room for
improvement in treatment of BM. At present, the standard treatment for inoperable/not
suitable for radiosurgery BM is whole-brain radiotherapy (WBRT), but with only a median
overall survival (OS) of 6 to 12 months and a high brain relapse rate ranging from 30% to
100%.
In MBC, 70% to 80% of patients with BM are presented with more than two brain metastatic
tumors and are not candidate for both surgical treatment and stereotactic radiosurgery (SRS).
Unlike patients with solitary or oligo-brain metastatic tumors, for whom the addition of
local treatments such as surgery or SRS has been shown to improve OS and relapse rate; for
patients with multiple brain metastases, WBRT remained the only standard treatment and
improvements are desperately awaited.
Brain was once considered as a "sanctuary" area for systemic drugs due to the protection of
blood-brain-barrier (BBB). Although some preclinical studies suggest that the BBB could be
disrupted during the growth of brain metastatic tumor, the amount of chemotherapy drugs be
delivered to brain tissue was still far lower than that could be achieved in serum.
Bevacizumab, a vascular endothelial growth factor antibody, has shown the ability to
"normalize" the peri-tumoral vessels in preclinical models. The investigators hypothesized
that with the addition of bevacizumab, the chemotherapy drugs-etoposide and cisplatin, which
were shown also to have some activity for BM-will be delivered more efficiently into the once
"sanctuary" brain parenchyma, thus increasing the efficacy of BM treatment.
Recently, the research team have demonstrated that bevacizumab preconditioning followed by
etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast
cancer progressing from radiotherapy by a multi-center phase II study. The basic concept of
preconditioning, as referred to starting bevacizumab 1 day before chemotherapy, is that
normalization effect takes time to mature. In that study, 35 patients were enrolled. Twenty
seven patients (77.2%; 95%CI 59.9-89.6) achieved brain tumor volumetric response, defined as
a ≥50% reduction in the volumetric sum of all measurable brain lesions in the absence of
increasing steroid use, development of new brain lesion, or progressive neurologic symptoms.
With a median follow-up of 11.0 months, the median CNS progression free survival (PFS) was
6.7 months (95% CI 5.1 to 8.3 months), and OS was 9.4 months (95% CI 7.3 to 11.5 months).
At present, lapatinib is the only molecular targeted agent proven effective for MBC patients
with BM. The CNS response rate of first-line lapatinib plus capecitabine was 65% in
WBRT-naïve, HER2-positive MBC patients with BM. However, the median CNS PFS is still
disappointingly short at 5.5 months and the result is limited to MBC patients who are
HER2-positive.
It has been demonstrated that brain tumor size is a predictor of WBRT failure. Given the high
response rate of BEEP for BM in our phase II trial, the investigators hypothesized that as
induction BEEP decreased the size of BM, the effectiveness of WBRT would also be enhanced.
This integrated approach will do greater benefit to MBC patients with BM, irrespective of
subtype. Hence, the investigators plan to conduct this randomized phase II trial to evaluate
the efficacy of induction BEEP followed by WBRT.
Sub study of A-PLUS: A Integrated Study of MRI and PET of The Brain in Evaluation of
Neurocognitive Outcomes of Patients with Brain Metastasis Treated by Radiotherapy and
Chemotherapy.
The participants of A-PLUS trial may be enrolled in an additional study of this trial. This
additional prospective study aims to investigate the neurocognitive outcomes of patients with
brain metastases treated by radiotherapy and chemotherapy. The evaluations include
neurocognitive assessments, serial MRI and FDG PET-CT (Integrated MR-PET) at before and after
the study treatment. A total of 80 participants will be enrolled. The study protocol was
approved by the NTUH REC, No. 201412046MINA.
